Gut associated lymphoid tissue (GALT) harbors the majority of lymphoid tissue in the body and is an important site for viral replication and severe depletion of memory CD4+ T cells in human immunodeficiency virus-1 (HIV) infection. Patients on HAART display incomplete viral suppression and significantly slower restoration of CD4+ T cells in GALT than in peripheral blood and this correlates with persistent immune activation. The mechanisms contributing to chronic immune activation and HIV persistence in GALT during therapy have not been fully defined. The overall objective of this revised competitive renewal application is to determine the mechanisms of enteropathogenesis that contribute to chronic immune activation and viral persistence in GALT of HIV infected patients during HAART. We hypothesize that chronic immune activation in GALT is due to impaired gut epithelium renewal, loss of specific CD4+ T cell subsets, and residual viral replication in HIV infected patients during HAART. There are 3 specific aims: In HIV infected patients with or without HAART, we will (1) determine HIV replication dynamics and viral genomic diversity in GALT compared to peripheral blood. (2) investigate the molecular mechanisms of impaired renewal of the intestinal epithelial barrier and defects in cell maturation/differentiation along the villus-crypt axis. (3) investigate the prevalence, immunophenotype, and function of Th17 CD4+ T cells, a critical component of mucosal immune defense. The proposal capitalizes on our experience in enteropathogenic studies of HIV infection, our success in enrollment and longitudinal gut mucosal studies in patients, expertise in mucosal immunology, multicolor flow cytometry, gene expression analysis, and molecular virology, as well as the expertise of our collaborators in HIV genomic analysis and HIV patient care. The proposed studies will provide insights into the mechanisms that link chronic immune activation to impaired restoration of the gut mucosal immune system and viral persistence in HIV infection. Findings from these studies will be valuable in the elucidation of novel correlates of protection against HIV disease and may impact the development of improved vaccine and therapeutic approaches. PUBLIC HEALTH RELEVANCE: Despite therapy, human immunodeficiency virus (HIV) is not completely eliminated from the body. We will examine the role of intestinal tissue in the persistence of HIV infection. Since the intestinal tissues contain most of the body's immune cells, persistent HIV infection leads to severe impairment of both digestive and immune function and may increase the rate of progression to AIDS.